Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation
Qiliang Xin, … , Chao Wang, Haibin Wang
Qiliang Xin, … , Chao Wang, Haibin Wang
Published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):175-189. https://doi.org/10.1172/JCI92862.
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Research Article Reproductive biology Article has an altmetric score of 1

Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation

Abstract

Natural and synthetic progestogens have been commonly used to prevent recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity. However, the clinical efficacy of progesterone and its analogs for maintaining pregnancy is variable. Additionally, the underlying cause of impaired endometrial progesterone responsiveness during early pregnancy remains unknown. Here, we demonstrated that uterine-selective depletion of BMI1, a key component of the polycomb repressive complex-1 (PRC1), hampers uterine progesterone responsiveness and derails normal uterine receptivity, resulting in implantation failure in mice. We further uncovered genetic and biochemical evidence that BMI1 interacts with the progesterone receptor (PR) and the E3 ligase E6AP in a polycomb complex–independent manner and regulates the PR ubiquitination that is essential for normal progesterone responsiveness. A close association of aberrantly low endometrial BMI1 expression with restrained PR responsiveness in women who had previously had a miscarriage indicated that the role of BMI1 in endometrial PR function is conserved in mice and in humans. In addition to uncovering a potential regulatory mechanism of BMI1 that ensures normal endometrial progesterone responsiveness during early pregnancy, our findings have the potential to help clarify the underlying causes of spontaneous pregnancy loss in women.

Authors

Qiliang Xin, Shuangbo Kong, Junhao Yan, Jingtao Qiu, Bo He, Chan Zhou, Zhangli Ni, Haili Bao, Lin Huang, Jinhua Lu, Guoliang Xia, Xicheng Liu, Zi-Jiang Chen, Chao Wang, Haibin Wang

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Figure 7

Aberrantly decreased endometrial BMI1 levels are often detected in spontaneously miscarrying women undergoing IVF treatment.

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Aberrantly decreased endometrial BMI1 levels are often detected in spont...
(A) Quantitative real-time PCR analysis of PR, BMI1, and E6AP from spontaneously miscarried endometrial tissues (n = 16) compared with those in unwanted normal pregnancy (n = 12). Data shown represent the mean ± SEM. (B and C) Western blot analysis of BMI1 protein level indicates that a large portion (7 of 16) of endometrial tissues from women with spontaneous miscarriage show an obviously decreased BMI1 expression in comparison with that in normal unwanted pregnancy. In C, data are presented as the ratio of BMI1 protein level to the level of β-actin. The values are shown as the mean ± SEM. (D and E) Immunostaining analysis of endometrial PR, BMI1, and E6AP expression in women with spontaneous miscarriage versus normal unwanted pregnancy. Number within the bar indicates the number of samples tested. The values are shown as the mean ± SEM. E, epithelium; S, stroma. Black scale bar: 100 μm. (F) Endometrial mRNA expression levels of progesterone-target genes, FOSL2, JUN, TGFB1, and IRS, are significantly reduced in women with spontaneous miscarriage who exhibit lower BMI1 expression. Number within the bar indicates the number of samples tested. Data represent the mean ± SEM (n = 3). *P < 0.05, independent-samples Student’s t test.